PRE-eclampsia
Eclampsia
Monitoring,
Prevention &
Treatment
Choice of antihypertensive
Phone: +1-604-875-305
Peter von Dadelszen
BMedSc, MBChB, DipObst, DPhil, FRANZCOG, FRCSC, FRCOG
Associate Professor of Obstetrics & Gynaecology, UBC
Consultant in Maternal-Fetal Medicine, BC Women’s
Co-Director, CFRI Reproduction & Healthy Pregnancy Cluster
Christchurch
PRE-EMPT
(PRE-eclampsia-Eclampsia Monitoring, Prevention & Treatment)
• Five objective, LMIC community interventionfocussed, pre-eclampsia project
• Funding:
– Bill & Melinda Gates Foundation
Why use antihypertensives?
• Maternal stroke risk associated with both severe
systolic and/or diastolic hypertension
– sBP >160mmHg
– dBP >110mmHg
CEMACH 2007
• Severe hypertension associated with placental
abruption and attendant maternal and perinatal
risks
• Severe hypertension is included in most definitions
of ‘severe’ pre-eclampsia, although such
classification systems are flawed
Menzies et al. Hypertens Pregnancy 2007
Why use antihypertensives?
• In non-severe pregnancy hypertension
– No clear evidence of benefit other than to
reduce the frequency of episodes of severe
hypertension
– May adversely effect fetal growth velocity
von Dadelszen et al. Lancet 2000
• Therefore, my focus will be on the
pharmacological management of severe
hypertension
The ‘ideal’ agent in rural &
remote settings
•
•
•
•
•
Oral administration
Reliable reduction in BP
Smooth reduction in BP
Rapid onset of action
Minimal overshoot
– BP in target range
• sBP 130-160mmHg
• dBP 80-110mmHg
From what can we choose?
• Hydralazine
• Beta-blockers (& alpha-/beta-blockers)
– Atenolol
– Labetalol
• Calcium channel blockers
– Nifedipine
• Alpha-methyldopa
• Angiotensin converting enzyme inhibitors
• Angiotensin-II receptor blockers
From what can we choose?
• Hydralazine
• Beta-blockers (& alpha-/beta-blockers)
– Atenolol
– Labetalol
• Calcium channel blockers
– Nifedipine
• Alpha-methyldopa
• Angiotensin converting enzyme inhibitors
• Angiotensin-II receptor blockers
– Risks of fetal renal toxicity and IUFD
From what can we choose?
• MgSO4 is NOT an antihypertensive
The ‘ideal’ agent in rural &
remote settings
•
•
•
•
•
Oral administration
Reliable reduction in BP
Smooth reduction in BP
Rapid onset of action
Minimal overshoot
– BP in target range
• sBP 130-160mmHg
• dBP 80-110mmHg
Oral administration
• Atenolol
– No adverse effects on fetal growth when used acutely
•
•
•
•
Labetalol
Methyldopa
Nifedipine capsules
Nifedipine intermediate acting
– PA/Retard
• Hydralazine
Modified from: Magee & Abdullah. Expert Opin Drug Saf 2004
The ‘ideal’ agent in rural &
remote settings
•
•
•
•
•
Oral administration
Reliable reduction in BP
Smooth reduction in BP
Rapid onset of action
Minimal overshoot
– BP in target range
• sBP 130-160mmHg
• dBP 80-110mmHg
Reliable reduction in BP
severe hypertension
• CCBs are more reliable than hydralazine in lowering
BP in pregnant women with severe hypertension
Magee et al. BMJ 2004
Duley et al. CDSR 2006
• Hydralazine appears more reliable than labetalol
Magee et al. BMJ 2004
• Methyldopa may be an agent of choice for severe
hypertension
Duley et al. CDSR 2006
Reliable reduction in BP
severe hypertension
• CCBs are more reliable than hydralazine in lowering
BP in pregnant women with severe hypertension
Magee et al. BMJ 2004
Duley et al. CDSR 2006
• Hydralazine appears more reliable than labetalol
Magee et al. BMJ 2004
• Methyldopa may be an agent of choice for severe
hypertension
Magee et al. BMJ 2004
Reliable reduction in BP
severe hypertension
• CCBs are more reliable than hydralazine in lowering
BP in pregnant women with severe hypertension
Magee et al. BMJ 2004
Duley et al. CDSR 2006
• Hydralazine appears more reliable than labetalol
Magee et al. BMJ 2004
• Methyldopa may be an agent of choice for severe
hypertension
– Widely used – routinely on EMLs
The ‘ideal’ agent in rural &
remote settings
•
•
•
•
•
Oral administration
Reliable reduction in BP
Smooth reduction in BP
Rapid onset of action
Minimal overshoot
– BP in target range
• sBP 130-160mmHg
• dBP 80-110mmHg
Smooth reduction in BP
• The ideal agent will reduce BP effectively and
over a relatively short period of time
– <60min
– Stabilise and reduce MAP by 10% per hour
• BP fall will not be precipitous
– Adverse maternal CNS effects
– Adverse fetal effects
Normal
Pregnancy
Early-onset
pre-eclampsia
The ‘ideal’ agent in rural &
remote settings
•
•
•
•
•
Oral administration
Reliable reduction in BP
Smooth reduction in BP
Rapid onset of action
Minimal overshoot
– BP in target range
• sBP 130-160mmHg
• dBP 80-110mmHg
‘Rapid’ onset of action
Drug
Dosage
Onset
Peak
Duration
24hr
Atenolol
25 – 50 mg
1hr
2-4hr
Labetalol
200 mg
20min – 2hr
1-4 hr
500 mg – 2 g
40 min
3-6hr
12-24hr
10 mg
30min
4hr
12hr
5 – 10 mg
5-10min
30min
6.5hr
Methyldopa
Nifedipine PA (or retard)
Nifedipine capsule
(dose dependent)
8-12hr
(dose dependent)
Modified from: Magee & Abdullah. Expert Opin Drug Saf 2004
The ‘ideal’ agent in rural &
remote settings
•
•
•
•
•
Oral administration
Reliable reduction in BP
Smooth reduction in BP
Rapid onset of action
Minimal overshoot
– BP in target range
• sBP 130-160mmHg
• dBP 80-110mmHg
Minimal overshoot
• CCBs less likely to cause overshoot than
hydralazine
Magee et al. BMJ 2004
• Beta-blockers less likely to cause overshoot
than hydralazine
Magee et al. BMJ 2004
• Nifedipine PA/Retard less likely to cause
overshoot than capsules?
Brown et al. AJOG 2002
– Small RCT
– End-point (‘in range BP’) measured at time PA
approaching maximal effect
On balance
• An intervention package should include 1 - 3 oral
antihypertensive agent(s)
• The choice for a single antihypertensive lies between
methyldopa, nifedipine, and another beta-blocker,
probably atenolol
– labetalol is not on EMLs
• Theoretical and practical reasons to have all available
– Combined CNS control, beta-blockade and vasodilatation
– Second effective agent for women whose BP is resistant to
another agent
• Reserve i.v. hydralazine for obtunded/comatose
women
PRE-EMPT
Objective 3
• CLIP (Community-Level Interventions for Pre-eclampsia)
– Cluster randomised controlled trial of community
level interventions for women with pre-eclampsia
– Aims
• Can
– identification,
– early risk stratification, and
– initiation of life-saving treatment at the community
level
• decrease pre-eclampsia-related maternal and perinatal
mortality in LMIC?
CLIP
• Intervention
– CLIP package of care
• Case recognition & triage
• Treatment of severe hypertension (sBP ≥160mmHg)
– Oral antihypertensive ? Atenolol; ? Nifedipine, ? Methyldopa
– Intramuscular MgSO4 (5g each buttock)
• Treatment of eclampsia
– Intramuscular MgSO4 (5g each buttock)
• Transfer into facilities offering evidence-based care
– Setting
• Community – community health workers
• Primary health units (not repeated)
The ‘ideal’ agent in rural &
remote settings
•
•
•
•
•
Oral administration
Reliable reduction in BP
Smooth reduction in BP
Rapid onset of action
Minimal overshoot
– BP in target range
• sBP 130-160mmHg
• dBP 80-110mmHg